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2842. Durable Efficacy of Two-Drug Regimen (2DR) of Dolutegravir (DTG) plus Lamivudine (3TC) in Antiretroviral Treatment-Naive Adults with HIV-1 Infection at 96 Weeks: Subgroup Analyses in the GEMINI Studies

ABSTRACT: Abstract Background At Weeks 48 and 96 in the GEMINI-1 and GEMINI-2 studies (Clinicaltrials.gov: NCT02831673 and NCT02831764), the 2DR of DTG+3TC was noninferior to the three-drug regimen of DTG + tenofovir/emtricitabine (TDF/FTC) in achieving plasma HIV-1 RNA < 50 c/mL in treatment-naïve adults. Methods GEMINI-1 and 2 are identical, global, double-blind, multicenter Phase III studies. Participants with screening HIV-1 RNA ? 500.00 c/mL were randomized to once-daily DTG+3TC or DTG+TDF/FTC, stratified by plasma HIV-1 RNA and CD4+ cell count. The primary endpoint was the proportion of participants with plasma HIV-1 RNA < 50 c/mL at Week 48 (Snapshot algorithm). We present a secondary endpoint analysis of efficacy at Week 96 by baseline disease and demographic characteristics. For the overall population, estimates and confidence intervals were based on a stratified analysis using Cochran–Mantel–Haenszel weights. Results In total, 714 and 719 adults were randomized and treated in GEMINI-1 and -2, respectively. Based on a 10% noninferiority margin, DTG+3TC was noninferior to DTG+TDF/FTC at Week 96 in both GEMINI-1 and -2 and in the pooled analysis. Response rates across baseline HIV-1 RNA subgroups were high and similar in both arms in the pooled analysis, including in participants with baseline HIV-1 RNA >100,000 c/mL (Table 1). Results were also generally consistent regardless of age, gender, or race. In the CD4+ ? 200 cells/mm3 subgroup, response rates were lower in the DTG+3TC group compared with DTG+TDF/FTC; most reasons for nonresponse were unrelated to virologic efficacy or treatment regimen. Across both studies, 11 participants on DTG+3TC and 7 on DTG+TDF/FTC met protocol-defined virologic withdrawal criteria through Week 96; none had treatment emergent integrase-strand-transfer-inhibitor or NRTI resistance mutations. Conclusion In GEMINI-1 and 2, DTG+3TC was noninferior to DTG+TDF/FTC in treatment-naïve adults at Week 96, demonstrating durable efficacy. The results of subgroup analyses of efficacy at Week 96 were generally consistent with overall study results, and further demonstrate that DTG+3TC is an effective initial treatment for HIV-infected patients across a spectrum of disease characteristics and patient populations. The studies are ongoing. Disclosures All Authors: No reported Disclosures.

SUBMITTER: van Wyk J

PROVIDER: S-EPMC6808746 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe 2-drug regimen dolutegravir + lamivudine was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine in achieving HIV-1 RNA <50 copies/mL in treatment-naive adults in the 48-week primary analysis of the GEMINI trials. We present results from the prespecified 96-week secondary analyses.SettingOne hundred eighty-seven centers in 21 countries.MethodsGEMINI-1 and GEMINI-2 are identical, double-blind phase III studies. Participants with screening HIV-1 RNA ?500,000 copies/mL were randomized 1:1 to once-daily dolutegravir + lamivudine or dolutegravir + tenofovir disoproxil fumarate/emtricitabine.ResultsAt week 96, dolutegravir + lamivudine (N = 716) was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine (N = 717) in achieving HIV-1 RNA <50 copies/mL (Snapshot algorithm; -10% noninferiority margin) in the pooled analysis (proportion of responders, 86.0% vs 89.5%, respectively; adjusted treatment difference [95% CI], -3.4% [-6.7 to 0.0007]), GEMINI-1 (-4.9% [-9.8 to 0.03]), and GEMINI-2 (-1.8% [-6.4 to 2.7]). Proportions of participants in the HIV-1 RNA ?50 copies/mL Snapshot category were largely unchanged from week 48 to 96. Eleven participants taking dolutegravir + lamivudine and 7 taking dolutegravir + tenofovir disoproxil fumarate/emtricitabine met confirmed virologic withdrawal criteria through week 96; none had treatment-emergent resistance mutations. Dolutegravir + lamivudine had a lower rate of drug-related adverse events than dolutegravir + tenofovir disoproxil fumarate/emtricitabine (19.6% vs 25.0%; relative risk ratio, 0.78; 95% CI: 0.64 to 0.95). Renal and bone biomarker changes favored dolutegravir + lamivudine.ConclusionsConsistent with 48-week data, dolutegravir + lamivudine demonstrated long-term, noninferior efficacy vs dolutegravir + tenofovir disoproxil fumarate/emtricitabine without increased risk of treatment-emergent resistance, supporting its use in treatment-naive HIV-1-infected individuals.

Project description:Abstract Background GEMINI 1 & 2 are global double-blind, multi-center phase III non-inferiority studies evaluating efficacy and safety of dolutegravir (DTG) + lamivudine (3TC) once daily in treatment-naive HIV-1-infected adults with Screening HIV-1 RNA ? 500,000 c/mL (ClinicalTrials.gov: NCT02831673/NCT02831764). Participants were randomized 1:1 to treatment with DTG+3TC or DTG + tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC). The primary endpoint was the proportion of participants with plasma HIV-1 RNA < 50 c/mL at Week 48 (Snapshot algorithm). DTG+3TC was non-inferior to DTG+TDF/FTC at Weeks 48 and 96. Here we evaluate the impact of treatment adherence on Week 48 virologic response (VR) within the GEMINI trials as a post-hoc analysis. Methods Adherence was estimated using pill counts data and categorized as follows: ? 90% vs < 90%. Week 48 VR was measured as % of participants with HIV-1 RNA < 50 c/mL by Food and Drug Administration Snapshot and by last on treatment viral load (VL) for the intention to treat–exposed population for which adherence could be derived. VR and differences between treatment arms within each adherence category were calculated along with exact unadjusted 95% confidence intervals. Results 5% of participants had < 90% adherence in both treatment arms. Baseline VL and CD4+ cell counts were similar across adherence categories. VR was lower in the < 90% adherence group than the ? 90% group, but not different between the 2 treatment arms within the same adherence category: In the low adherence group, DTG+3TC VR was 69% compared to 65% in DTG+TDF/FTC arm by Snapshot and 91% and 85% respectively by last on treatment VL analysis (Table). Table. Conclusion In the GEMINI studies, a lower Week 48 VR was observed in participants with < 90% adherence, but the impact of lower adherence on VR was similar in the DTG+3TC compared with DTG+TDF/FTC arms. One limitation of the analysis is the small number of participants in the lower adherence subgroup. However, the results add further information about the robustness of DTG+3TC compared to 3-drug DTG-containing regimens and may suggest similar regimen forgiveness. Disclosures Mounir Ait-Khaled, PhD, ViiV Healthcare (Employee, Shareholder) Choy Man, BSc, ViiV Healthcare (Employee, Shareholder) Jorg Sievers, DPhil, ViiV Healthcare (Employee) Richard Grove, MSc, GSK/ViiV (Employee, Shareholder) Brian Wynne, MD, ViiV Healthcare (Employee) Rimgaile Urbaityte, MSc, GlaxoSmithKline (Employee, Shareholder) Jean A. van Wyk, MB,ChB, ViiV Healthcare (Employee, Shareholder) Debbie Hagins, MD, Gilead Sciences Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)Janssen (Grant/Research Support)Merck (Consultant, Grant/Research Support, Advisor or Review Panel member)Viiv Healthcare (Consultant, Grant/Research Support, Advisor or Review Panel member) Andrew Zolopa, MD, ViiV Healthcare (Employee)

Project description:BackgroundA dolutegravir (DTG)-based antiretroviral regimen has been rolled out for pregnant women in low- and middle-income countries since 2020. However, available safety data are limited to a few clinical trials and observational studies. Hence, we present real-world pregnancy and birth outcome safety data from a large sample multicenter cohort study in Ethiopia.MethodsA retrospective cohort study was conducted in fourteen hospitals across Ethiopia from 2017 to 2022. HIV-infected pregnant women were followed from the date of prevention of mother-to-child transmission (PMTCT) care enrolment until the infant was 6-8 weeks old. The primary safety outcome was a composite of adverse pregnancy events comprising spontaneous abortion, intrauterine fetal death (IUFD) before onset of labor, preterm birth, and maternal death. Additionally, a composite adverse birth outcome was assessed, comprising intrapartum fetal demise, low birth weight, and neonatal death. Finally, a composite of adverse pregnancy or birth outcome was also investigated. The exposure of interest was the antiretroviral treatment (ART) regimen used during pregnancy for PMTCT of HIV.ResultsDuring the study period, 2643 women were enrolled in routine PMTCT care. However, 2490 (92.2%) participants were eligible for the study. A total of 136/1724 (7.9%, 95% CI: 6.7-9.3%) women experienced adverse pregnancy outcomes. Fewer women in the DTG-based group (5.4%, 95% CI: 3.7-7.5%) had adverse pregnancy outcomes than in the Efavirenz (EFV)-based group (8.3%, 95% CI: 6.6-10.3%), P = 0.004. After controlling for baseline differences, the DTG group had a 43% lower risk of adverse pregnancy outcomes (adjusted odd ratio (AOR), 0.57; 95% CI, 0.32-0.96%) and a 53% lower risk of preterm birth (AOR, 0.47; 95% CI, 0.22-0.98%) compared to the EFV group. A total of 103/1616 (6.4%, 95% CI: 5.2-7.7%) women had adverse birth outcomes. Although the difference was not statistically significant, fewer women in the DTG group (30/548; 5.5%, 95% CI: 3.7-7.7%) than in the EFV group (57/830; 6.9%, 95% CI: 5.2-8.8%) had adverse birth outcomes.ConclusionsIn this study, we observed that DTG-based regimens were associated with better pregnancy and birth outcome safety profiles, reaffirming the WHO recommendation. However, a prospective study is recommended to assess uncaptured maternal and perinatal adverse outcomes, such as congenital abnormalities, and infant growth and neurocognitive development.

Project description:BackgroundTherapy with tenofovir is associated with lower bone mineral density (BMD), higher markers of bone turnover and increased fracture risk in HIV-infected adults. Bone structural parameters generated by hip structural analysis may represent a separate measure of bone strength, but have not been assessed in HIV.MethodsDual-energy X-ray absorptiometry (DXA) scans from 254 HIV-infected adults randomised to simplify their existing dual nucleoside analogue reverse transcriptase inhibitor therapy to coformulated tenofovir-emtricitabine or abacavir-lamivudine were analysed using DXA-derived hip structural analysis software. Hip structural parameters included femoral strength index, section modulus, cross-sectional area, and cross-sectional moment of inertia. We used one-way ANOVA to test the relationship between nucleoside analogue type at baseline and structural parameters, multivariable analysis to assess baseline covariates associated with femoral strength index, and t-tests to compare mean change in structural parameters over 96 weeks between randomised groups.ResultsParticipants taking tenofovir at baseline had lower section modulus (-107.3 mm2, p = 0.001), lower cross-sectional area (-15.01 mm3, p = 0.001), and lower cross-sectional moment of inertia (-2,036.8 mm4, p = 0.007) than those receiving other nucleoside analogues. After adjustment for baseline risk factors, the association remained significant for section modulus (p = 0.008) and cross-sectional area (p = 0.002). Baseline covariates significantly associated with higher femoral strength index were higher spine T-score (p = 0.001), lower body fat mass (p<0.001), lower bone alkaline phosphatase (p = 0.025), and higher osteoprotegerin (p = 0.024). Hip structural parameters did not change significantly over 96 weeks and none was significantly affected by treatment simplification to tenofovir-emtricitabine or abacavir-lamivudine.ConclusionIn this population, tenofovir use was associated with reduced composite indices of bone strength as measured by hip structural analysis, but none of the structural parameters improved significantly over 96 weeks with tenofovir cessation.Trial registrationClinicalTrials.gov NCT00192634.

Project description:The two-drug regimen dolutegravir plus lamivudine demonstrated durable efficacy for up to 3 years in phase III studies and a high barrier to resistance in treatment-naive and virologically suppressed people with HIV (PWH). This systematic literature review summarizes real-world evidence evaluating effectiveness and safety of dolutegravir plus lamivudine. We searched Ovid MEDLINE®, Embase®, PubMed, Cochrane library, and relevant international conference proceedings from 2013 to 2020. Qualitative synthesis of virologic suppression at Week 48, treatment-emergent resistance, discontinuation rates, and comorbidities was undertaken, with no statistical analyses conducted. Linked publications and potential for duplication in reporting of outcomes for cohorts and populations were identified, and the publication reporting the highest number of PWH receiving dolutegravir plus lamivudine was included in the analysis. Thirty-four studies reporting on cohorts of PWH not suspected to be linked or to include duplicate data receiving dolutegravir plus lamivudine were identified (N = 5017). Of 3744 virologically suppressed PWH who switched to dolutegravir plus lamivudine, 603 (16%) reported history of virologic failure. Nineteen studies included effectiveness data (n = 3558), four of which included data from treatment-naive PWH (n = 69). In studies with > 100 PWH, high rates of virologic suppression (Week 48, 97-100%) were maintained with dolutegravir plus lamivudine, with low rates of virologic failure (0-3.3 per 100 person-years of follow-up); one instance of emergent integrase strand transfer inhibitor resistance was reported in a complex treatment-experienced individual. Rates of discontinuation due to adverse events were low and consistent with previously observed trial data. Dolutegravir plus lamivudine minimally impacted renal function and had minimal impact on or improved lipid profiles and bone mineral density. This systematic review demonstrates that effectiveness and safety of dolutegravir plus lamivudine in clinical practice support data from randomized controlled trials with regard to high rates of virologic response, low rates of discontinuation, and a high barrier to resistance.

Dataset Information

2842. Durable Efficacy of Two-Drug Regimen (2DR) of Dolutegravir (DTG) plus Lamivudine (3TC) in Antiretroviral Treatment-Naive Adults with HIV-1 Infection at 96 Weeks: Subgroup Analyses in the GEMINI Studies

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